3-45491566-C-G

Position:

• chr3-45491566-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015340.4(LARS2):​c.1289C>G​(p.Ala430Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: LARS2 NM_015340.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56

Genes affected

LARS2 (HGNC:17095): (leucyl-tRNA synthetase 2, mitochondrial) This gene encodes a class 1 aminoacyl-tRNA synthetase, mitochondrial leucyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. [provided by RefSeq, Jul 2008]

LARS2-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4	c.1289C>G	p.Ala430Gly	missense_variant	13/22	ENST00000645846.2	NP_056155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2	c.1289C>G	p.Ala430Gly	missense_variant	13/22		NM_015340.4	ENSP00000495093.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;.;D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;.;D;.;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L;L;.;L;L
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D;D;D;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.30	T;T;T;.;.
Sift4G	Benign	0.096	T;T;T;.;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.67
MutPred		0.70		Gain of methylation at R431 (P = 0.0741);Gain of methylation at R431 (P = 0.0741);.;Gain of methylation at R431 (P = 0.0741);Gain of methylation at R431 (P = 0.0741);
MVP		0.62
MPC		0.83
ClinPred		0.90	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879255606; hg19: chr3-45533058;